Carboxylic acid amides, compositions and medical use thereof

ABSTRACT

Amide derivatives of non-steroidal anti-inflammatory carboxylic acids which have anti-inflammatory activity in their own right as well as being effective as pro-drugs of the carboxylic acids.

This is a division of application Ser. No. 839,255 filed Mar. 13, 1986,U.S. Pat. No. 4,783,487

This invention relates to amide derivatives of certain non-steroidalanti-inflammatory carboxylic acids.

One problem associated with some non-steroidal anti-inflammatorycarboxylic acids is that they tend to cause gastric irritation. Anotherproblem associated with compounds of this class is that they have arelatively short duration of action. Certain conditions where thepatient is suffering from chronic inflammation, require a prolongedlevel of active drug in order to provide the desired level of painrelief.

We have now discovered a class of amide derivatives of non-steroidalanti-inflammatory carboxylic acids which have anti-inflammatory activityin their own right as well as being effective as pro-drugs of thecarboxylic acids. The activity displayed by the compounds is sustainedover a relatively long period.

Furthermore amides are relatively stable to metabolism in thegastro-intestinal tract. The compounds are absorbed intact and are splitin the liver to produce the free non-steroidal anti-inflammatory acidwhich is partially absorbed directly from the hepatic blood circulationand partly returned by the bile to the lower gastro-intestinal tract. Inthis way the local irritant effect on the stomach is significantlyreduced.

One mechanism by which non-steroidal anti-inflammatory agents operate isthrough the inhibition of prostaglandin biosynthesis. One consequence ofadministering non-steroidal anti-inflammatories is that arachidonicacid, a substrate from which prostaglandins are formed, is diverted intoa cascade of enzymatic transformations resulting in the production ofleukotrienes.

Leukotrienes cause bronchoconstriction. The administration ofnon-steroidal anti-inflammatory drugs that block prostaglandin synthesiswithout blocking leukotriene inhibition results in a condition calledrespiratory distress syndrome. A further advantage of the compounds ofthis invention is that they block leukotriene synthesis and hence avoidthe development of this syndrome.

According to the present invention there is provided compounds offormula (1): ##STR1## and pharmaceutically acceptable salts and estersthereof where

R¹ is a single bond or a substituted or unsubstituted alkanediyl group,

R² is a substituted pyrrolyl, thienyl or pyridyl group or a group offormula (2): ##STR2## where R⁵ represents hydrogen or a substituent,

R⁶ represents a substituent or

R⁵ and R⁶ together represent the residue of a mono- or bicyclic ring;

the group R² being such that the group of formula (3):

    R.sup.2 --R.sup.1 CO                                       (3)

represents the residue of a non-steroidal anti-inflammatory carboxylicacid.

The compounds of formula (1) are non-steroidal anti-inflammatory agentsand have the anti-inflammatory, analgesic and anti-pyretic propertiesassociated with this class of compounds. They are useful for thetreatment of musculo-skeletal disorders especially rheumatoid arthritis,osteoarthritis, periarthritis, tendinitis, tenosynovitis and bursitis.

The group of formula (3):

    R.sup.2 --R.sup.1 CO                                       (3)

where R¹ and R² are as defined with reference to formula (1) is derivedfrom a non-steroidal anti-inflammatory carboxylic acid of formula (4):

    R.sup.2 --R.sup.1 COOH                                     (4)

where R¹ and R² are as defined with reference to formula (1).

Throughout this specification, the position of the group R² is numberedrelative to the--R¹ CONH--moiety.

One class of compounds is that where R² is a substituted pyridyl groupand R¹ is a covalent bond. For example, it can be2-(3-trifluoromethylphenylamino)-3-pyridyl, that is, the group offormula (3) is derived from nifluminic acid.

A further class of compounds within the scope of this invention is whereR² is a substituted pyrrolyl or thienyl group and R¹ is a substituted orunsubstituted alkanediyl group. In particular R² is1-p-chlorophenyl-2,5-dimethyl-3-pyrrolyl and R¹ is methylene, that is,the group of formula (3) is derived from clopirac or R² is1-methyl-5-p-toluoyl-2-pyrrolyl and R¹ is methylene, that is, the groupof formula (3) is derived from tolmetin, or R² is 5-benzoyl-2-thienyland R¹ is ethane-1,1-diyl, that is, the group of formula (3) is derivedfrom tiaprofenic acid.

A further class of compounds within the scope of this invention is whereR² is a subsituted indenyl group. In particular it can be5-fluoro-3-methyl-1-[p-(methylsulfinyl)benzylidene]-3-indenyl, that is,the group of formula (3) is derived from sulindac.

A further class of compounds within the scope of this invention is whereR² is a substituted indolyl group and R¹ is methylene. In particular R²can be 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl, that is, thegroup of formula (3) is derived from indomethacin or R² is3-(p-chlorobenzoyl)-6-methoxy-2-methyl-1-indolyl, that is, the group offormula (3) is derived from clometacin, or it is1-cinnamoyl-5-methoxy-2-methyl-3 -indolyl, that is, the group of formula(3) is derived from cinmetacin.

A further group of compounds within the scope of this invention is whereR² --R¹ CO represents a group of formula (5): ##STR3##

One class of compounds within the scope of this invention is where R¹ isa single bond.

A sub-group of compounds within this group is where R⁵ is hydrogen andR⁶ is in position 2. Examples of such compounds are where R⁶ is2-acetoxy, that is the group of formula (5) is derived fromacetylsalicylic acid; or R⁶ is 2-(3-trifluoromethylphenylamino) that isthe group of formula (5) is derived from flufenamic acid; or R⁶ is2-(2,6-dichloro-4-methylphenylamino) that is the group of formula (5) isderived from meclofenamic acid; or R⁶ is 2-(2,3-dimethylphenylamino)that is where the group of formula (5) is derived from mefenamic acid.

A second sub-group of compounds where R² --R¹ CO is a group of formula(5) where R¹ is a covalent bond is where R⁵ is a hydroxyl group inposition 2, and R⁶ is a 5-(2,4-difluorophenyl) group that is the groupof formula (5) is derived from diflunisal.

A further group of compounds of formula (1) where R² --R¹ CO is a groupof formula (5) is where R¹ is methylene. Within this class R⁵ can behydrogen and R⁶ can be 2-(2,6-dichlorophenylamino) that is the group offormula (5) is derived from dichlofenac, or R⁵ can be 3-chloro and R⁶can be 4-allyloxy that is the group of formula (5) is derived fromalclofenac, or R⁵ and R⁶ together represent the residue of a10-methylphenothiazine group that is the group of formula (5) is derivedfrom metiazinic acid.

A further group of compounds within the scope of this invention where R²--R¹ CO is a group of formula (5) is where R¹ is ethane-1,1-diyl. Withinthis group of compounds, R⁵ can be hydrogen and R⁶ can be 3-phenoxy,that is the group of formula (5) is derived from phenoxyprofen, or R⁶ is4-(2-methylpropyl) that is the group of formula (5) is derived fromibuprofen or R⁶ is 1-oxo-2-isoindolyl that is the ggroup of formula (5)is derived from indoprofen.

A further sub-group within the group of compounds of formula (1) whereR² --R¹ CO is a group of formula (5) is where R¹ is ethane-1,1-diyl andR⁵ and R⁶ together represent the residue of a7-methoxy-10-methylphenothiazine group, that is the group of formula (5)is derived from protizinic acid or R⁵ and R⁶ together represent theresidue of a 6-methoxynaphthyl group so that the group of formula (5) isderived from naproxen.

Preferably the group of formula (5) is derived from diclofenac oribuprofen.

Particularly preferred compounds of formula (1) are:N-(1-carboxy-2hydroxy-5-phenyl)-2-[(2,6-dichlorophenyl)amino]acetamideN-(1-carboxy-2-hydroxy-5-phenyl)-2-(4-isobutylphenyl)-propionamideN-(1-carboxy-2-hydroxy-5-phenyl)-d-2-(6-methoxy-2-naphthyl)propionamide,andN-(1-carboxy-2-hydroxy-5-phenyl)-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetamide.

The phenolic hydroxyl group is acidic and like the carboxyl group canform salts with bases. In addition, the hydroxyl and carboxyl group canalso form esters. Reference to pharmaceutically acceptable salts andesters herein means a salt or ester of the hydroxyl or carboxyl group orboth.

Examples of salts are alkali-metal salts for example the sodium salt andalkaline-earth metal salts for example the magnesium salt.

Examples of ester groups for the hydroxyl group are acetyl and propionylesters.

Examples of ester groups for the carboxyl group are C₁₋₄ alkyl groupsespecially methyl, ethyl and propyl.

5-Aminosalicylic acid is the active principle in the compoundsulphasalazine which has been used in the treatment of Crohn's diseaseand ulcerative colitis. One of the original therapeutic uses ofsulphasalazine was as a disease modifying agent for the treatment ofarthritis, that is an agent which can arrest the progress of thedisease, and it has been reintroduced for this purpose. Recently it hasbeen found that sulphasalazine is metabolized in vivo to produce5-aminosalicylic acid and sulphapyridine. In Crohn's disease andulcerative colitis 5-aminosalicylic acid is responsible for thetherapeutic acitivity of sulphasalazine whereas sulphapyridine isresponsible for the main side effects. Thus 5-aminosalicylic acid andcompounds which give rise to it in vivo may also be particularly usefulin the treatment of arthritis.

5-Aminosalicylic acid is relatively unstable and therefore difficult touse as a therapeutic agent in its own right. An advantage of thecompounds of this invention is that while the group R² --R¹ CO has astabilising effect on the 5-aminosalicylic acid moiety, the acids R²--R¹ CO₂ H do not have the undesired side effects associated withsulphasalazine. So the compounds of this class provide in a singlemolecule two different therapeutic principles free of their mostsignificant disadvantages.

The compounds of formula (1) can be prepared by reacting a non-steroidalanti-inflammatory carboxylic acid of formula (4):

    R.sup.2 --R.sup.1 COOH                                     (4)

where R¹ and R² are as defined with reference to formula (1) or anactivated esterifying derivative thereof with a compound of formula (6):##STR4## where R³ is hydroxyl or is a protected hydroxyl group and R⁴ iscarboxyl or a protected carboxyl group, where necessary in the presenceof an acylation catalyst, thereafter removing any protecting groups fromthe groups R³ or R⁴ and optionally converting the hydroxyl and carboxylgroups into a pharmaceutically acceptable salt or ester.

Examples of acylating derivatives of compounds of formula (4) are acidhalides and mixed anhydrides.

Examples of acylation catalysts are in particular condensation reagentsused in peptide chemistry for example dicyclohexylcarbodiimide andespecially 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

The use of protecting groups is discussed in J. F. McOmie, ProtectiveGroups in Organic Chemistry, 1973, Plenum Press, IBSN 0-306-30717-0.

Preferably the reaction is carried out in the presence of an organicsolvent at moderate temperature using one molar equivalent of thecompounds of formulae (4) and (6).

Compounds of formula (1) can be converted into pharmaceuticallyacceptable salts by standard methods for example reaction with a baseand into pharmaceutically acceptable esters by reaction with anesterifying agent.

The starting materials of formulae (4) and (6) are known or can be madeby analogy with known methods.

The ability of the compounds of this invention to reduce inflammationcan be demonstrated in vivo using the rat's paw carrageenin oedema testas described by Hofrichter et al, Arzn. Forsch. 1969, 19, 2016, andWinter et al, Proc. Soc. Exp. Biol. Med. 111, 544 (1962). The compoundof Example 1 can reduce swelling by more than 50% at a dose of 29.2 mgkg⁻¹ i.g.

The potential usefulness of the compounds for treating chronicinflammation in arthritic conditions can be assessed using the standardadjuvant arthritis test in the rat. The compound of example 1 wasadministered at a dose of 0.73 mg/kg daily for 14 days: oedema at theaffected right hind paw as well as the secondary reaction on the lefthind paw was reduced significantly compared to controls (p 0.05) and thedecrease in body weight associated with the arthritic condition wassignificantly suppressed.

The effect of the compounds on the incidence and severity ofindomethacin-induced intestinal ulcers was tested according to themethod of Del Soldato, Agents and Actions, 16, 393-396. Afteradministration of indomethacin (16 mg/kg) rats pretreated with thecompound of Example 1 (1 50 mg/kg) showed intestinal ulceration in 61%of cases compared with 92% of control rats. Pretreatment with thecompound of Example 1 at a dose level of 400 mg/kg totally suppressedulcer development.

The ability of the compounds of this invention to reduce inflammationcan be demonstrated in vitro by measuring their ability to inhibitprostaglandin synthesis in cultured macrophages by the method describedby Brune et al, Archives of Pharmacol. 1981, 315, 269. The compound ofExample 1 can reduce PGE₂ production by over 20% at doses of 3.3×10⁻⁶molar.

The ability of the compounds of this invention to inhibit leukotrienesynthesis can be demonstrated in vitro using the mouse peritonealmacrophage test described by Brune et al, Agents and Actions 1984, 14,729.

In order to use the compounds of the invention as anti-inflammatoryagents, they can be formulated as pharmaceutical compositions inaccordance with standard pharmaceutical procedure.

The invention also includes pharmaceutical compositions comprising acompound of formula (1) or a pharmaceutically acceptable salt or anester thereof and a pharmaceutically acceptable carrier. In addition,the invention includes a method of treating inflammation byadministering to a mammal an effective but non-toxic amount of acompound of formula (1) or a pharmaceutically acceptable salt or anester thereof and a method of treating rheumatoid arthritis orosteoarthritis by administering said compounds.

Compounds of formula (1) can be administered topically or systemically.

Topical formulations for administration to the skin include lotions andcreams.

Systemic administration can be achieved by rectal, oral or parenteraladministration. A typical suppository formulation comprises the activecompound with a binding agent and/or lubricating agent for examplegelatine or cocoa butter or other low melting vegetable waxes or fats.Typical parenteral compositions consist of a solution or suspension ofthe active material in a sterile aqueous carrier or parenterallyacceptable oil.

Compounds of formula (1) which are active when given orally can beformulated as syrups, tablets, capsules and lozenges. A syrupformulation generally consists of a suspension or solution of thecompound in a liquid carrier for example ethanol, glycerine or waterwith a flavouring or colouring agent. Where the composition is in theform of a capsule, the solid in granular form optionally with a bindingagent is encased in a gelatin shell. Where the composition is in theform of a tablet, any suitable pharmaceutical carrier routinely used forpreparing solid formulations can be used. Examples of such carriersinclude magnesium stearate, starch, lactose, glucose, sucrose, andcellulose. Preferably the composition is in unit dose form for example atablet or capsule so that the patient may administer to himself a singledose.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned, in this case as anti-inflammatory agents for the treatmentof, for example, rheuamtoid arthritis, osteoarthritis, periarthritis,tendinitis, tenosynovitis and bursitis.

Each dosage unit for oral administration contains preferably from 5 to200 mg of a compound of formula (1).

The compounds of the invention will normally be administered to asubject for the treatment of rheumatoid arthritis, osteoarthritis,periarthritis, tendinitis, tenosynovitis and bursitis. An adult patientwill receive an oral dose of between 15 mg and 400 mg and preferablybetween 15 mg and 200 mg or an intravenous, subcutaneous orintramuscular dose of between 1 mg and 50 mg, and preferably between 1mg and 10 mg of a compound of formula (1), the composition beingadministered 1 to 4 times per day.

The following Examples illustrate the invention.

Example 1

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g) wasadded to a chilled (0°) suspension of 5-aminosalicylic acid (1.6 g),diclofenac (2.9 g) and triethylamine (1.0 g) in dichloromethane (200 ml)with stirring.

The mixture was stirred for 3 hrs. The reaction mixture was washed withhydrochloric acid (0.1N) to remove the triethylamine and unreacted5-aminosalicylic acid. The organic layer was isolated, dried and thesolvent removed. The residue was recrystallised from methanol/water toyield N-(1-carboxy-2-hydroxy-5-phenyl)-2-[(2,6-dichlorophenyl)amino]acetamide (1.4 g, 30%) m.p. 260° as a white powder. This compound wassoluble in ethanol, acetone and aqueous alkali and had λ_(max) (ethanol)254 nm.

Example 2

Substituting ibuprofen (5.2 g) for diclofenac in the process of Example1 and using 5-aminosalicylic acid (3.06 g), triethylamine (2.09 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.95 g) inmethylene chloride (200 ml) yieldedN-(1-carboxy-2-hydroxy-5-phenyl)-2-(4-isobutylphenyl)propionamide (1.5g, 20%) m.p. 238° C.; M⁺ (m.s.) 341.

Example 3

Substituting naproxen (7.07 g) for diclofenac in the process of Example1 and using 5-aminosalicylic acid (4.72 g), triethylamine (3.15 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.88 g) inmethylene chloride (200 ml) yieldedN-(1-carboxy-2-hydroxy-5-phenyl)-d-2-(6-methoxy-2-naphthyl) propionamide(2.4 g; 20%) m.p. 220° C.; M⁺ (m.s.) 365.

Example 4

Substituting indomethacin (3.52 g) for diclofenac in the process ofExample 1 and using 5-aminosalicylic acid (1.66 g), triethylamine (1.13g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.94g) in methylene chloride (100 ml) yieldedN-(1-carboxy-2-hydroxy-5-phenyl)-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetamide,(1.1 g, 20%) m.p. 256 ° C.; M⁺ (m.s.) 492.

Example 5

A tablet for oral administration is prepared by combining

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        N--(1-carboxy-2-hydroxy-5-phenyl)-                                                                   100                                                    2-[(2,6-dichlorophenyl)amino] acetamide                                       Mannitol               153                                                    Starch                 33                                                     Polyvinyl pyrollidone  12                                                     Microcrystalline cellulose                                                                           30                                                     Magnesium Stearate     2                                                      ______________________________________                                    

into a tablet using standard pharmaceutical procedures.

What is claimed is:
 1. The compoundN-(1-carboxy-2-hydroxy-5-phenyl)-2-[(2,6-dichlorophenyl)amino]acetamideand pharmaceutically acceptable salts and esters thereof.
 2. Apharmaceutical composition comprising a non-toxic but therapeuticallyeffective amount of the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 3. A method of treating musculo-skeletal disordersin a mammal, which method comprises administering to said mammal atherapeutically effective but non-toxic amount of the compound ofclaim
 1. 4. The method of claim 3 wherein the musculo-skeletal disorderis rheumatoid arthritis or osteoarthritis.
 5. A method of treatinginflammation in a mammal, which method comprises administering to saidmammal a therapeutically effective but non-toxic amount of the compoundof claim 1.